The lessebo effect in randomized controlled trials of rituximab in patients with rheumatoid arthritis:...

The goal of this study was to assess the impact of negative expectations associated with receiving a placebo (the lessebo effect) on efficacy outcomes in randomized clinical trials (RCTs) of rituximab in patients with rheumatoid arthritis (RA).

We performed a meta-analysis on the American College of Rheumatology 20%, 50%, and 70% (ACR20, 50, 70) response rates in the placebo and active (biosimilar)-controlled groups (reference-pbo and reference-bs) of rituximab showing an insufficient response to methotrexate or tumor necrosis factor. We evaluated the difference in ACR20, 50, 70 response rates between the two groups (reference-bs vs. reference-pbo).

Nine RCTs included a total of 2734 patients with RA. The pooled incidence of ACR20 response rate in the placebo- and active-controlled groups of the rituximab RCTs for RA was 53.1% (95% confidence interval [CI] 49.9-56.3%) and 75.0% (95% CI 71.2-78.4%), respectively. The difference in the ACR20 response rate between the placebo- and active-controlled groups was -20.9% (95% CI -26.9 to 61.9%, p < 0.001). The pooled incidence of ACR50 response rate in the placebo- and active-controlled groups of the rituximab RCTs for RA was 29.0% (95% CI 26.2-32.0%) and 47.4% (95% CI 43.2-51.6%), respectively. The ACR50 response rates were significantly higher in the active-controlled groups than in the placebo-controlled groups (-18.4%; 95% CI -18.4 to -13.4%, p < 0.001). The difference in the ACR70 response rate between the placebo- and active-controlled groups was -14.9% (95% CI -22.2 to -7.6%, p < 0.001). The ACR20, 50, 70 response rates were significantly higher in the active-controlled groups than in the placebo-controlled group.

This study shows that the use of a placebo can be associated with a clinically significant reduction in the magnitude of change of the ACR20, 50, 70 response rates in rituximab RCTs for RA. The lessebo effect has potential implications for the development of new treatments and appraisal of current treatment options for RA.